Editors' ChoiceIon Channels

PIEZO1 promotes inflammation

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Science Signaling  10 Sep 2019:
Vol. 12, Issue 598, eaaz4154
DOI: 10.1126/scisignal.aaz4154

Myeloid cells respond to mechanical force through the ion channel PIEZO1, which promotes their proinflammatory response.

Mechanical force alters the functions of blood vessels, epithelial cells, and neurons. Solis et al. now find that myeloid immune cells also sense mechanical force through the pressure-sensitive ion channel PIEZO1 (see commentary by Walmsley). In macrophages exposed to pressure cycles, but not static pressure, expression of the gene encoding PIEZO1 was increased. In the absence of PIEZO1, macrophages and monocytes exposed to pressure cycles did not express inflammatory cytokines and chemokines or the transcription factor hypoxia-inducible factor 1α (HIF-1α). Similarly, exposing macrophages to cyclical pressure in calcium-free medium or after blocking PIEZO1 activity with an inhibitor also prevented HIF-1α accumulation. Classical supernatant-transfer experiments showed that a small, secreted factor promoted pressure-stimulated HIF-1α stabilization, and the hormone endothelin-1 (EDN1) was secreted by macrophages in a PIEZO1-dependent manner in response to cyclical pressure. Pharmacological inhibition or genetic disruption of the EDN1 receptor or the kinase JNK limited pressure-stimulated HIF-1α activation in macrophages. In mice, conditional loss of PIEZO1 in myeloid cells exacerbated infection with the bacterium Pseudomonas aeruginosa, which correlated with reduced amounts of inflammatory cytokines and EDN1 in lung lavage fluid, as well as reduced amounts of HIF-1α in inflammatory monocytes. Antibody-mediated depletion of monocytes reduced the abundance of EDN1 and the neutrophil-recruiting chemokine CXCL12 in the lung fluid of mice after infection. Furthermore, intranasal administration of recombinant EDN1 reversed bacterial accumulation in the lungs and liver of mice lacking PIEZO1. Loss of PIEZO1 in myeloid cells also reduced EDN1 accumulation and lung fibrosis in bleomycin-treated mice. Together, these data show how myeloid cells can sense changes in pressure and mechanical force, which occur upon tissue entry and can drive proinflammatory responses independently of innate immune pattern recognition.

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